The etiology and pathogenesis of schizophrenia in the sense of the above definition are to date unknown. In fact there is agreement about the important role of genetic influences, however a series of presumably relevant co-factors is known, for example neurotrauma, drug consumption etc. which appear to have an influence on the outbreak of the disease. In particular the molecular and cellular mechanisms which play a role pathogenetically in this disease are also unknown. No really good animal models for schizophrenia have therefore been produced to date. The available animal models cover merely partial aspects of the disease.
It is therefore the object of the present invention to make available a method for treating schizophrenia and related psychoses and also a means for treating schizophrenia and related psychoses.
This object preferably is achieved by the characterizing features of the present invention. Advantageous embodiments and further developments of the solution will be apparent from the description of the invention provided herein.
There is thereby understood by schizophrenia actual and/or chronic schizophrenia and related psychoses. By treatment there should be considered not only the treatment in the case of symptoms which have already occurred but also the prophylactic use in the case of people who are particularly at risk, for example in the case of people with a high hereditary factor, with neurotrauma (e.g. brain injury), psychotrauma and the like.
The proposed medicinal neuroprotection in schizophrenia is thereby a generally completely new therapeutic and prophylactic starting point. This takes into account the observation confirmed again and again by epidemiologists and clinicians that, already in the course of the first episode of the disease, a dramatic impairment of cognitive/mental function happens which is at least partially irreversible and levels off generally in the further episodes rather on a constant or a less progressive level. Here now the consistent use of a neuroprotective therapy approach intervenes also as “add-on therapy” in conjunction with a symptom-arresting neuroleptic, particularly in the first episode of the psychosis. A preventive use of erythropoietin in the people particularly at risk is also proposed according to this invention.
Evidence of the importance of the use of erythropoietin (EPO) as means of prevention of schizophrenia and related psychoses has been further established in recent scientific literature published by the inventor. Both publications are incorporated herein by reference. Sirén A.-L., Radyushkin K., Boretius S., Kämmer D., Riechers C.-C., Natt O., Sargin D., Takashi W., Sperling S., Michaelis T., Price J., Meyer B., Frahm J. and Ehrenreich H., Brain 129: 480-89 (2006) show that EPO can prevent global brain atrophy after unilateral parietal lesion in the mammalian brain (mouse model). EPO given to lesioned animals abolished the cognitive dysfunction, as tested, for example, by the Morris water maze task, seen in animals not administered EPO.
In conjunction with the shown results in an animal, the inventor has also published the results of EPO administration in chronic schizophrenic patients (Ehrenreich H., Hinze-Selch D., Stawicki S., Aust C., Knolle-Veentjer S., Wilms S., Heinz G., Erdag S., Jahn H., Degner D., Ritzen M., Mohr A., Wagner M., Schneider U., Bohn M., Huber M., Czernik A., Pollmächer T., Maier W., Siren A.-L., Klosterkötter J., Falkai P., Rüther E., Aldenhoff J. B. and Krampe H., Molecular Psychiatry 12:206-220 (2007). The use of recombinant human EPO at dosages proscribed in the parent application, once a week for 12 weeks resulted in improved cognitive function, as measured, for example, by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) in these patients.
These published studies were carried out to show a “proof-of-principle.” It should be clear that the invention outlined in the parent application and the further inventive claims of this continuation-in-part (CIP) are not only plausible, but very promising tools in the treatment and prevention of schizophrenia and its related psychoses.
Erythropoietin, also described in brief as “EPO”, is a glycoprotein occurring naturally in the body with a molecular weight of 34,000 daltons (W. Jelkmann, “Erythropoietin: Structure, Control of Production, and Function”, Physiological Reviews, 1992, Volume 72, pages 449 to 489). It is an essential growth factor for the production of erythrocytes and was isolated for the first time already in 1977.
There are a plethora of substances, which all are considered to increase or prolong the activation and/or stimulation of erythropoietin receptors. Besides erythropoietin itself, whether native or recombinant, whether in native sequence or even after sequence changes or sequence shortening, erythropoietin analogs, erythropoietin fragments or erythropoietin agonists were developed. As examples for recombinant EPO, Epoetin a (Epogen by Amgen Inc., Procrit by Ortho Biotech Inc., Johnson and Johnson Inc.), Epoetin β (Neorecormon by Hoffmann-LaRoche AG) and Epoetin ω (Epomax), Epoetin δ (DynEpo, Shire Pharmaceuticals Group Plc.) with varying glycosilation and sialysation are known. Genetically modified EPO are known as Darbepoetin α (Amgen Inc.) and CERA (Hoffmann-LaRoche AG). Further, erythropoietin receptor activating antibody (e.g. by Abbott), fusion proteins like Epo-Fc and carbamylated EPO (CEPO, Lundbeck A/S) are known. Further, endogenous erythropoietin stimulating substances, substances increasing the release and/or activity of endogenous erythropoietin (e.g. HIF-stabilizers, e.g. by Fibrogen Inc. or Torrent Pharmaceuticals Ltd.) are also known. Furthermore, erythropoietin analogs or mimetics are known, e.g. SEP (Synthetic Erythropoiese Protein by Gryphon Therapeutics) or Hematide (by Affymax Inc.) and others known as EPO-analogs or -mimetics by AplaGen. It is even known to transfer the gene coding for erythropoietin into a patient in order to express erythropoietin.
All of these substances are known to increase and/or prolong the activation and/or stimulation of the EPO receptor besides their antiapoptotic, tissueprotective effect. Some useable EPO variants are published for example in the following publications, which are incorporated herein by reference:
Leist et al., Science 2004, Vol. 305, pp. 239-242, WO 86/03520, WO 85/02610, WO 90/11354, WO 91/06667, WO 91/09955, WO 93/09222, WO 94/12650, WO 95/31560. WO 95/05465.
Also, incorporated herein by reference is an overview of known variants, analogs, mimetics and equivalents which can also be used in their entirety in the present invention and also of known fields of use thereof appears in Brines and Cerami, Nature Review, Neuroscience, June 2005, Vol. 6, pp. 484-494.
The term erythropoietin in the scope of this invention is meant to describe any agent that increases and/or prolongs the activation and/or stimulation of any kind of erythropoietin receptor. This would include any of the substances described or referenced above.
Erythropoietin has been in frequent clinical use for many years in nephrodialysis in the case of patients who have renal anemia, for obtaining fairly large quantities of autologous blood before planned operations and it also hit the press headlines as a sports drug.
Erythropoietin thereby proved to be exceptionally well tolerated. In particular, the frequently therapeutically desired stimulation of the hematopoiesis with polyglobulin and also an arterial hypertonia which is rarely to be seen should be mentioned as a relevant side-effect. Both effects are to be expected mainly after chronic erythropoietin administration. These are remedied when required relatively simply by medicinal treatment or blood-letting. Intolerance reactions or anaphylactic reactions in the case of erythropoietin constitute rarities.
As a fairly large protein with a molecular weight of approximately 34,000 daltons erythropoietin is considered as generally not being able to easily surmount the blood-brain barrier. A directly intracerebroventricular administration of erythropoietin, i.e. direct infusion of erythropoietin into the brain tissue is ruled out however in human beings usually, because of risks which are involved in the installation and the maintenance of a temporary ventricular drainage, such as infections or hemorrhages.